Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
  • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/06—Antimigraine agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the present invention relates to a combination comprising as components (a) at least one 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound, and (b) at least one antiepileptic, a pharmaceutical formulation and a dosage form comprising said combination as well as a method of treating pain, e.g. neuropathic pain, wherein components (a) and (b) are administered simultaneously or sequentially to a mammal, whereby component (a) may be administered before or after component (b) and whereby components (a) or (b) are administered to the mammal either via the same or a different pathway of administration.
• pain e.g. neuropathic pain
• WO 01/13904 describes substance combinations comprising a tramadol material and an anticonvulsant drug, which show super-additive effects upon administration. Due to the super-additive effect the overall dose and accordingly the risk of undesired side effects can be reduced.
• a combination comprising (a) at least one 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound, and (b) at least one antiepileptic exhibits an analgesic effect. If these components are present in the composition in such a weight ratio that a supra-additive or synergistic effect is observed upon administration to the patients, the overall administered dose may be lowered, so that fewer undesired side-effects will occur.
• the present invention relates to a pharmaceutical combination comprising as components
• the compound 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol according to component (a) may be present in the inventive pharmaceutical composition in form of an acid addition salt, whereby any suitable acid capable of forming such an addition salt may be used.
• Suitable acids include but are not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid and/or aspartic acid.
• Salt formation is preferably effected in a solvent, for example, diethyl ether, diisopropyl ether, alkyl acetates, acetone and/or 2-butanone.
• a solvent for example, diethyl ether, diisopropyl ether, alkyl acetates, acetone and/or 2-butanone.
• trimethylchlorosilane in aqueous solution is also suitable for the preparation of hydrochlorides.
• Antiepileptics which are often also referred to as anticonvulsants, are well known in the art and include, without limitation, barbiturates and derivatives, such as methylphenobarbital, phenobarbital, primidone, barbexaclone and metharbital; hydantoin derivatives such as ethotoin, phenytoin, amino(diphenylhydantoin) valeric acid, mephenytoin and fosphenytoin; oxazolidine derivatives such as paramethadione, trimethadione and ethadione; succinimide derivatives such as ethosuximide, phensuximide and mesuximide; benzodiazepine derivatives such as clonazepam; carboxamide derivatives such as carbamazepine, oxcarbazepine, eslicarbazepine and rufinamide; fatty acid derivatives such as valproic acid, valpro
• antiepileptics include, for example, mexiletin, retigabin and ralfinamide. Some antiepileptics are known to be useful in the treatment of neuropathic pain. In one embodiment of the present invention one or more of these antiepileptics is used as component (b).
• stereoisomers also included are stereoisomers, salts, solvates, polymorphs and derivatives of the antiepileptic component as well as mixtures of any of the foregoing.
• the antiepileptic according to component (b) is selected from the group consisting of pregabalin, and gabapentin,
• the antiepileptic according to component (b) is pregabalin.
• the antiepileptic according to component (b) is (S)-pregabalin.
• Another specific embodiment of the present invention is a combination comprising (a) (1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, or an acid addition salt thereof such as the hydrochloride addition salt, and (b) pregabalin.
• Yet another specific embodiment of the present invention is a combination comprising (a) (1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, or an acid addition salt thereof such as the hydrochloride addition salt, and (b) (S)-pregabalin.
• Some antiepileptics comprise functional groups, for example, acidic groups such as carboxy groups which are capable of forming salts with the 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol component of formula (I), thereby incorporating both components (a) and (b) in one and the same salt.
• acidic groups such as carboxy groups which are capable of forming salts with the 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol component of formula (I), thereby incorporating both components (a) and (b) in one and the same salt.
• the inventive combination comprises components (a) and (b) in form of a salt formed from these two components.
• a salt formation may be partial, i.e. the inventive composition comprises one or both of these components also in their non-salt form, or the salt formation may essentially be complete.
• Both components (a) and (b) as part of the inventive combination may be administered in amounts up to their maximum daily dosage, which is known to those skilled in the art.
• the compound Pregabalin may preferably be administered to a patient in a daily dosage of 1 to 1200 mg
• the compound Gabapentin may preferably be administered to a patient in a daily dosage of 1 to 5000 mg.
• the compound (1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol may preferably be administered to a patient in a daily dosage of 25 to 1000 mg, particularly preferably in a dosage of 50 to 800 mg, more particularly preferably in a dosage of 100 to 600 mg.
• the administered amount per day of component (a) and/or component (b) may be less than the respective maximum daily dosage and be, for example, 75 ⁇ 15 wt.-%, 75 ⁇ 10 wt.-%, 75 ⁇ 5 wt.-%, 50 ⁇ 15 wt.-%, 50 ⁇ 10 wt.-%, 50 ⁇ 5 wt.-%, 25 ⁇ 15 wt.-%, 25 ⁇ 10 wt.-% and 25 ⁇ 5 wt.-% for each of the components.
• the inventive combination may contain components (a) and (b) essentially in an equieffective ratio.
• inventive combination components (a) and (b) are present in such a weight ratio that the resulting composition will exert a supra-additive or synergistic effect upon administration to a patient.
• Suitable weight ratios can be determined by methods well known to those skilled in the art.
• Both components (a) and (b) may also be present in the inventive combination in ratios deviating from the equieffective ratio.
• each of the components could be present in a range from 1/50 of the equieffective amount to 50 times the equieffective amount, from 1/20 of the equieffective amount to 20 times the equieffective amount, from 1/10 of the equieffective amount to 10 times the equieffective amount, from 1/5 of the equieffective amount to 5 times the equieffective amount, from 1/4 of the equieffective amount to 4 times the equieffective amount, from 1/3 of the equieffective amount to 3 times the equieffective amount, or from 1/2 of the equieffective amount to 2 times the equieffective amount.
• components (a) and (b) can be administered in a specific dosage regimen to treat pain, for example, neuropathic pain.
• Components (a) and (b) may be administered simultaneously or sequentially to one another, in each case via the same or different administration pathways.
• Another aspect of the present invention is therefore a method of treating pain, characterized in that components (a) and (b) are administered simultaneously or sequentially to a mammal, wherein component (a) may be administered before or after component (b) and wherein components (a) or (b) are administered to the mammal either via the same or a different pathway of administration.
• pain as used herein includes but is not limited to inflammatory pain, neuropathic pain, acute pain, chronic pain, visceral pain, migraine pain and cancer pain.
• Suitable pathways of administration include but are not limited to oral, intravenous, intraarterial, intraperitoneal, intradermal, transdermal, intrathekal, intramuscular, intranasal, transmucosal, subcutaneous, and rectal administration.
• the inventive combinations are toxicologically safe and are therefore suitable for the treatment of mammals, particularly humans including infants, children and grown-ups.
• the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising an inventive combination as described herein and one or more auxiliary agents.
• the present invention relates to a pharmaceutical dosage form comprising an inventive combination as described herein and one or more auxiliary agents.
• inventive pharmaceutical dosage form additionally comprises caffeine.
• the inventive pharmaceutical dosage form is suitable for being administered orally, intravenously, intraarterially, intraperitoneally, intradermally, transdermally, intrathekally, intramuscularly, intranasally, transmucosally, subcutaneously, or rectally.
• auxiliary agents for example, carriers, fillers, solvents, diluents, colorants and/or binders.
• auxiliary agents for example, carriers, fillers, solvents, diluents, colorants and/or binders.
• the selection of auxiliary agents and of the amounts of the same to be used depends, for example, on how the drug is to be administered, e.g. orally, intravenously, intraarterially, intraperitoneally, intradermally, transdermally, intramuscularly, intranasally or locally, for example for infections of the skin, of the mucous membranes or of the eye.
• Suitable auxiliary agents in the context of this invention are in particular any substances known to a person skilled in the art useful for the preparation of galenical formulations.
• suitable auxiliary agents include but are not limited to: water, ethanol, 2-propanol, glycerol, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, glucose, fructose, lactose, saccharose, dextrose, molasses, starch, modified starch, gelatine, sorbitol, inositol, mannitol, microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose, cellulose acetate, shellac, cetyl alcohol, polyvinyl pyrrolidone, paraffins, waxes, natural and synthetic gums, acacia gum, alginates, dextran, saturated and unsaturated fatty acids, stearic acid, magnesium stearate, zinc stearate, glycerol stearate, sodium la
• compositions in the form of tablets, effervescent tablets, chewing tablets, dragees, capsules, drops, juices or syrups are, for example, suitable for oral administration.
• Oral pharmaceutical formulations may also be in the form of multiparticulates such as granules, pellets, spheres, crystals and the like, optionally compressed into a tablet, filled into a capsule, filled into a sachet or suspended in a suitable liquid medium.
• Oral pharmaceutical formulations may also be equipped with an enteric coating.
• compositions that are suitable for parenteral, topical and inhalative administration include but are not limited to solutions, suspensions, easily reconstitutable dry preparations and sprays.
• Suppositories are a suitable pharmaceutical formulation for rectal administration.
• Formulations in a deposit, in dissolved form, for example, in a patch optionally with the addition of agents to promote skin penetration, are examples of suitable formulations for percutaneous administration.
• inventive pharmaceutical formulations may be produced using materials, means, devices and processes that are well known in the prior art of pharmaceutical formulations, as described for example in " Remington's Pharmaceutical Sciences", A.R. Gennaro (ed.), 17th edition, Mack Publishing Company, Easton, Pa. (1985), in particular in part 8, chapters 76 to 93 .
• the components of the pharmaceutical composition may be granulated with a pharmaceutical carrier, for example conventional tablet ingredients such as corn starch, lactose, saccharose, sorbitol, talcum, magnesium stearate, dicalcium phosphate or pharmaceutically acceptable gums, and pharmaceutical diluents, for example water, in order to form a solid composition that contains the components in homogeneous distribution.
• a pharmaceutical carrier for example conventional tablet ingredients such as corn starch, lactose, saccharose, sorbitol, talcum, magnesium stearate, dicalcium phosphate or pharmaceutically acceptable gums, and pharmaceutical diluents, for example water
• homogeneous distribution is taken to mean that the components are distributed uniformly over the entire composition, so that said composition may easily be divided into equally effective unit dose forms, such as tablets, pills or capsules and the like.
• the solid composition is then divided into unit dose forms.
• compositions having a corresponding release profile may be prepared.
• An example of such a formulation is an osmotically driven release system for achieving a delayed release of one component via a coating that itself contains the other component which is accordingly released earlier.
• a release system of this kind which is particularly suitable for oral administration, at least part, and preferably all, of the surface of the release system, preferably those parts that will come into contact with the release medium, is/are semipermeable, preferably equipped with a semipermeable coating, so the surface(s) is/are permeable to the release medium, but substantially, preferably entirely, impermeable to the active ingredient, the surface(s) and/or optionally the coating comprising at least one opening for releasing the active ingredient.
• precisely that/those surface(s) that is/are in contact with the release medium is/are provided with a coating containing and releasing the other component.
• This is preferably taken to mean a system in tablet form comprising a release opening, an osmotic pharmaceutical composition core, a semipermeable membrane and a polymer portion that exerts pressure upon swelling.
• a suitable example of this kind of system is the system distributed by ALZA Corporation, USA under the tradenames OROS®, in particular, the OROS® Push-PullTM System, the OROS® Delayed Push-PullTM System, the OROS® Multi-Layer Push-PullTM system, the OROS® Push-Stick System and also, in specific cases, the L-OROSTM.
• Embodiments and examples of osmotically driven release systems are, for example, disclosed in US patents 4,765,989 , 4,783,337 and 4,612,008 ,
• a further example of a suitable pharmaceutical formulation is a gel-matrix tablet, such as the products developed by Penwest Pharmaceuticals (for example, under TimeRX). Suitable examples are provided in US patents 5,330,761 , 5,399,362 , 5,472,711 and 5,455,046 , Particularly suitable is a retarding matrix formulation, with an inhomogeneous distribution of the pharmaceutically active composition, whereby, component (a) can be distributed in the outer region (the portion that comes into contact with the release medium most quickly) of the matrix and the other component is distributed inside the matrix. On contact with the release medium, the outer matrix layer initially (and rapidly) swells and firstly releases the first component, followed by the significantly (more) retarded release of the other component.
• a suitable matrix include matrices with 1 to 80 % by weight of one or more hydrophilic or hydrophobic polymers as pharmaceutically acceptable matrix formers.
• a further example of a suitable matrix may be inferred from US 4,389,393 .
• the amount of the inventive pharmaceutically active combination to be administered to the patient may vary depending on different factors well known to those skilled in the art, for example, the weight of the patient, the route of administration, or the severity of the illness.
• the present invention relates to the use of an inventive combination as described herein for the treatment of pain, said pain preferably including but not being limited to inflammatory pain, neuropathic pain, acute pain, chronic pain, visceral pain, migraine pain and cancer pain.
• the present invention relates to the use of an inventive combination as described herein for the preparation of a medicament for the treatment of pain, said pain preferably including but not being limited to inflammatory pain, neuropathic pain, acute pain, chronic pain, visceral pain, migraine pain and cancer pain.
• the present invention relates to a method of treating pain in a mammal, preferably a human, which comprises administering an effective amount of an inventive combination as described herein to the mammal.
• the weight ratios of components (a) and (b) that will lead to a supra-additive effect/synergistic effect of the inventive compositions may be determined in the test of Kim & Chung as described in Kim SH, Chung JM. An experimental model for peripheral mononeuropathy produced by segmental spinal nerve ligation in the rat. Pain 1992; 50: 355-63 . Said reference is hereby incorporated by reference and forms part of the disclosure.
• tapentadol hydrochloride or tapentadol-HCI
• S-pregabalin as well as the inventive combination of tapentadol-HCI and (S)-pregabalin were each dissolved in 0.9 % NaCl solution and injected by the intravenous (i.v.) route (application volume 5 ml/kg).
• Tapentadol hydrochloride (0.1, 0.316, 1, 3.16 and 10 mg/kg i.v.) showed a dose dependent increase in the withdrawal threshold of the ipsi-lateral hind paw with an efficacy of 94 % MPE and an ED 50 -value (95 % confidence interval) of 1.65 (1.20 - 2.35) mg/kg i.v. calculated from the peak effect vs. control values at 30 min. after administration.
• (S)-Pregabalin (0.1, 3.16 and 10 mg/kg i.v.) showed a dose dependent increase in the withdrawal threshold of the ipsi-lateral hind paw with an efficacy of 67% MPE and an ED 50 -value (95 % confidence interval) of 4.20 (3.37 - 5.43) mg/kg i.v. calculated from the peak effect vs. control values at 30 min. after administration.
• Tapentadol hydrochloride and (S)-pregabalin show a potency difference which amounts to a factor 2.5 based on the ED 50 values 30 minutes after administration.
• Combinations in a fixed ratio of 1 : 2.5 (tapentadol hydrochloride : (S)-pregabalin) were tested in doses of 0.1 mg/kg + 0.25 mg/kg; 0.3 mg/kg + 0.75 mg/kg, 1 mg/kg + 2.5 mg/kg i.v. tapentadol hydrochloride + (S)-pregabalin, respectively. These combinations showed a dose dependent increase in the withdrawal threshold of the ipsi-lateral hind paw. The highest dose combination tested showed full efficacy with 89 % MPE. Potency was quantified by an ED 50 value (95 % confidence interval) of 0.83 (0.74 - 0.92) mg/kg i.v. calculated from the peak effect vs control values at 30 min after administration.
• Table 1 Experimental ED 50 values of tapentadol hydrochloride and (S)-pregabalin and isobolographic analysis of the interaction between tapentadol hydrochloride and (S)-pregabalin: tapentadol-HCl (S)-pregabalin
• Substance / ED 50 [mg/kg i.v.] (95 % confidence interval) 1.65 (1.20-2.35) 4.20 (3.37 - 5.43) 2.91 (2.28-3.54) 0.83 (0.74-0.92) synergistic (p ⁇ 0.001)
• p Level of statistical significance
• the experimental ED 50 value (95 % confidence interval) of 0.83 (0.74 - 0.92) mg/kg i.v. of the inventive combination is below the theoretical additive ED 50 value (95 % confidence interval) of 2.91 (2.28 - 3.54) mg/kg i.v. and is statistically significant (p ⁇ 0.001) as compared to the line of additivity.
• the interaction of tapentadol hydrochloride and (S)-pregabalin is synergistic.

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